Familial MDS/AML is a group of rare Mendelian disorders associated with strong predisposition to MDS and/or AML. The genetic basis of these disorders is explained in ~50% of these families by inherited variants in three genes {RUNX1, CEBPA, or GATA2). Affected carriers in these families develop MDS/AML with variable latency and incomplete penetrance, suggesting that cooperating somatic mutations are required for transformation. We hypothesize that there are additional high penetrance germline alleles that account for familial MDS/AML cases lacking known causal variants. In Specific Aim 1, we will identify novel inherited genetic variants associated with familial MDS/AML. We have assembled a large number of MDS/AML kindreds (>40), with known causes identified in approximately half. We will use an innovative screen to exclude known causes in the remaining families and will then perform whole genome sequencing to identify novel variants in all cases with unexplained familial predisposition. We will identify variants that segregate with MDS/AML in these families and test for replication in other families. We will generate extended pedigrees for early-onset de novo AML cases, determine the extent of familial aggregation of MDS/AML and other cancers, and mine germline whole genome sequence data generated for these cases by other GAML projects to identify additional inherited risk alleles for AML. We will perform functional studies to characterize the effects of novel alleles on hematopoiesis. In Specific Aim 2, we will define the landscape of somatic genetic alterations in familial MDS/AML. We will perform whole genome sequencing of paired tumor/normal samples from at least 50 cases of familial MDS/AML and compare the spectrum of somatic mutations in these cases to de novo and therapy-related MDS/AML. Knowledge gained from this project will inform our understanding ofthe biology of AML, and lead to better strategies for surveillance, early detection, and treatment of MDS/AML, including optimized stem cell donor selection in families with inherited susceptibility.